ACVIM consensus statement on the diagnosis of immune thrombocytopenia in dogs and cats

Abstract

Immune thrombocytopenia (ITP) is the most common acquired primary hemostatic disorder in dogs. Immune thrombocytopenia less commonly affects cats but is an important cause of mortality and treatment-associated morbidity in both species. Immune thrombocytopenia remains a diagnosis of exclusion for which diagnostic guidelines are lacking. Primary, or non-associative, ITP refers to autoimmune platelet destruction. Secondary, or associative, ITP arises in response to an underlying disease trigger. However, evidence for which comorbidities serve as ITP triggers has not been systematically evaluated. To identify key diagnostic steps for ITP and important comorbidities associated with secondary ITP, we developed 12 Population Evaluation/Exposure Comparison Outcome (PECO) format questions. These questions were addressed by evidence evaluators utilizing a literature pool of 287 articles identified by the panelists using a structured search strategy. Evidence evaluators, using panel-designed templates and data extraction tools, summarized evidence and created guideline recommendations that then were integrated by diagnosis and comorbidity domain chairs. The revised PECO responses underwent a Delphi survey process to reach consensus on final guidelines. A combination of panel expertise and PECO responses were employed to develop algorithms for diagnosis of ITP in dogs and cats, which also underwent 4 iterations of Delphi review. Comorbidity evidence evaluators employed an integrated measure of evidence (IME) tool to determine evidence quality for each comorbidity; IME values combined with evidence summaries for each comorbidity were integrated to develop ITP screening recommendations, which also were subjected to Delphi review. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The final consensus statement provides clinical guidelines for the diagnosis of, and underlying disease screening for, ITP in dogs and cats. The systematic consensus process identified numerous knowledge gaps that should guide future studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Treatment of Immune Thrombocytopenia.

Keywords: autoimmune; hemostasis; immune‐mediated; platelet; thrombopoietin.

FIGURE 1

(A) Overview of the methodology of the Diagnosis Domain. (B) Overview of the methodology of the Comorbidity Domain. EE, evidence evaluator; IME, integrated metric of evidence; PECO, Population, Exposure/Evaluation, Comparison, Outcome question.

FIGURE 2

An algorithm for the diagnosis of ITP in dogs. ^aThrombocytopenia should be confirmed with a slide assessment. In brief, to perform a platelet estimate, first assess the slide body and feathered edge under low magnification for clumps, the presence of which suggests that the platelet count is falsely low. Resampling is then warranted, if possible. If there are no clumps, a platelet count is estimated by calculating the mean number of platelets per 10 oil immersion fields (×100) in the body of the smear where erythrocytes are spread in monolayer and multiplying this number by 15 000 to 20 000 to obtain the number of platelets per microliter; ^bthe magnitude of thrombocytopenia is consistent with consumption from major hemorrhage. However, it is possible that DIC, vasculitis, sequestration, or ITP may be contributing; ^cconsider genetic testing; ^dexcludes additional cytopenias with plausible explanations for example, pre‐regenerative anemia in the face of acute hemorrhage or hemolysis or lymphopenia in an ill/stressed patient; ^esampling of bone marrow by aspiration, core biopsy, or both, is undertaken; ^ffor example, lymphoreticular neoplasia or ehrlichiosis; ^gat least 2 of 5 parameters abnormal in addition to thrombocytopenia: prothrombin time (PT), activated partial thromboplastin time (aPTT), D‐dimers > reference interval (RI); antithrombin, fibrinogen < RI; ^hPT or aPTT >25% control value or upper bound of RI; ⁱpartial screening (ie, not exhaustive) for potential trigger factors undertaken and negative.

FIGURE 3

An algorithm for the diagnosis of ITP in cats. ^aThrombocytopenia should be confirmed with a slide assessment. In brief, to perform a manual count first assess the slide's feathered edge under low magnification for clumps, the presence of which suggests that the platelet count is falsely low. Resampling is then warranted, if possible. If there are no clumps, a platelet count is estimated by calculating the mean number of platelets per 10 oil immersion fields (×100) and multiplying this number by 15 000 to 20 000 to obtain the number of platelets per microliter; ^bthe magnitude of thrombocytopenia is consistent with consumption from major hemorrhage; this is a rare association in cats. However, it is possible that DIC, vasculitis, sequestration, or ITP may be contributing; ^cexcludes additional cytopenias with plausible explanations for example, pre‐regenerative anemia in the face of acute hemorrhage or hemolysis or lymphopenia in an ill/stressed patient; ^dsampling of bone marrow by aspiration, core biopsy, or both, is undertaken; ^efor example, lymphoreticular neoplasia or feline immunodeficiency virus infection; ^fat least 2 of 4 parameters abnormal in addition to thrombocytopenia: prothrombin time (PT), activated partial thromboplastin time (aPTT), D‐dimers > reference interval (RI); fibrinogen < RI; ^gPT or aPTT >25% control value; ^hpartial screening (ie, not exhaustive) for potential trigger factors undertaken and negative.

FIGURE 4

Summary of evidence for the causal role of comorbidities as a trigger for ITP in dogs and cats. Level of evidence for a specific comorbidity as a cause of ITP was assessed by means of a published Integrated Metric of Evidence (IME) value, which captures information on study design, quality of reporting, confidence of comorbidity diagnosis, likelihood of a causal link between the comorbidity and ITP, confidence of the ITP diagnosis, and the number of patients with a given comorbidity (excluding those patients with more than 1 comorbidity). Horizontal dotted lines indicate threshold IME values between negligible and low (3.15), low and intermediate (4.57), and intermediate and high (5.81) levels of evidence based on predetermined hypothetical thresholds (Supporting Information 8). An IME value of 0 indicates that the study directly demonstrated a lack of evidence that a comorbidity caused ITP.

FIGURE 5

Summary of evidence for the causal role of infection as a trigger for ITP in dogs. Level of evidence for infection with a specific pathogen (or location/type of infection) as a cause of ITP was assessed by means of a published Integrated Metric of Evidence (IME) value. Horizontal dotted lines indicate threshold IME values between negligible and low (3.15), low and intermediate (4.57), and intermediate and high (5.81) levels of evidence based on predetermined thresholds (Supporting Information 8). An IME value of 0 indicates that the study directly demonstrated a lack of eidence that a comorbidity caused ITP.

FIGURE 6

Summary of evidence for the causal role of drugs as a trigger for ITP in dogs. Level of evidence for drugs as a cause of ITP was assessed by means of a published Integrated Metric of Evidence (IME) value. Horizontal dotted lines indicate threshold IME values between negligible and low (3.15), low and intermediate (4.57), and intermediate and high (5.81) levels of evidence based on predetermined thresholds (Supporting Information 8). An IME value of 0 indicates that a study directly demonstrted a lack of evidence that a comorbidity caused ITP.